Novel combination of an ADP-receptor blocking antiplatelet drug and a thromboxane A2 receptor antagonist and a method for inhibiting thrombus formation employing such combination

Abstract

A method is provided for inhibiting platelet aggregation and thrombus formation by administering to a patient an ADP-receptor blocking antiplatelet drug, such as clopidogrel, in combination with a thromboxane A 2 receptor antagonist, such as ifetroban, and optionally a cholesterol lowering drug, such as an HMG CoA reductase inhibitor, for example, pravastatin.

What is claimed is:  
     
         1 . A pharmaceutical combination comprising an ADP-receptor blocking antiplatelet drug and a thromboxane A 2  receptor antagonist.  
     
     
         2 . The combination as defined in  claim 1  wherein the antiplatelet drug is clopidogrel or ticlopidine or 2-acetoxy-5-(α-cyclopropylcarboxyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.  
     
     
         3 . The combination as defined in  claim 1  wherein the thromboxane A 2  receptor antagonist is ifetroban or vapiprost.  
     
     
         4 . The combination as defined in  claim 1  wherein the thromboxane A 2  receptor antagonist is a 7-oxabicyclo-heptane substituted amino-prostaglandin analog, a 7-oxabicycloheptane substituted diamide prostaglandin analog, an interphenylene 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analog, a 7-oxabicyclo-heptyl substituted heterocyclic amide prostaglandin analog, or a 7-oxabicycloheptane imidazole prostaglandin analog.  
     
     
         5 . The combination as defined in  claim 4  wherein the thromboxane A 2  receptor antagonist is [1S-[1α, 2α(Z)),3α((1E, 3S*, 4R*), 4α]]-7-[3-(3-hydroxy-4-phenyl-1-pentenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; has the name [1S-[1α, 2α(Z),3α, 4α]]-7-[3-[[[[(1-oxoheptyl)-amino]acetyl]amino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the corresponding tetrazole; [1S-[1α, 2α((Z), 3α, 4α]]-7-[3-[[[[(4-cyclohexyl-1-oxobutyl)-amino]acaetyl]amino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; [1S-[1α, 2α(Z), 3α, 4α]]-7-[3-[[2-(phenyl-amino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; [1S-(1α, 2α, 3α, 4α)]-2-[[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoic acid (SQ 33,961), or esters or salts thereof; [1S-(1α, 2α, 3α, 4α)]-2-[[3-[4-[[[4-chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo [2.2.1]hept-2-yl]methyl]benzenepropanoic acid or esters, or salts thereof; [1S-(1α, 2α, 3α, 4α)]-3-[[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2:1]hept-2-yl]methyl]benzeneacetic acid, or esters or salts thereof; [1S-(1α, 2α, 3α, 4α)]-[2-[[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenoxy]acetic acid or esters or salts thereof; [1S-(1α, 2α, 3α, 4α)]-2-[[3-[4-[[(7,7-dimethyloctyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-[1α, 2α(Z), 3α, 4α]]-6-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α, 2α(Z), 3α, 4α]]-6-[3-[[4-(4-cyclohexyl-1-hydroxybutyl)-1H-imidazol-l-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid or its methyl ester; [1S-[1α, 2α(Z), 3α, 4α]]-6-[3-[[4-(3-cyclohexyl-propyl)-1H-iomidazol-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid or its methyl ester; [1S-[1α, 2α(Z), 3α, 4α]]-6-[3-[[4-(4-cyclohexyl-1-oxobutyl)-1H-imidazol-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid or its methyl ester; [1S-[1α, 2α(Z), 3α, 4α]]-6-[3-(1H-imidazol-1-ylmethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid or its methyl ester; [1S-[1α, 2α(Z), 3α, 4α]]-6-[3-[[4-[[(4-cyclohexylbutyl)amino]-carbonyl]-1H-imidazol-1-yl]methyl-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or its methyl ester; (E)-5-[[[(pyridinyl)[3-(trifluoromethyl)phenyl]methylene]amino]-oxy]pentanoic acid (R 68,070); [1S-[1α(Z), 2β, 3β, 5α]]-(+)-7-[5-([1,1′-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid (GR 32,191 Vapiprost); 4(Z)-6-[(2,4,5-cis)2-(2-chlorophenyl)-4-(2-hydroxyphenyl)1,3-dioxan-5-yl]hexenoic acid (ICI 192,605); 7-[2α, 4α-(dimethylmethano)-6β-(2-cyclopentyl-2β-hydroxyacetamido)-1α-cyclohexyl]-5(Z)-heptenoic acid (ONO 3708); or 3-[[(4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid (BAY u 3405) ramatroban; (±)(5Z)-7-[3-endo-[(phenylsulfonyl)amino]bicyclo[2.2.1]-hept-2-exo-yl]heptenoic acid (domitroban), (−)6,8-difluoro-9-p-methylsulfonylbenzyl-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid (L670596, Merck) and (3-[l-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]-2,2-dimethylpropanoic acid (L655240, Merck).  
     
     
         6 . The combination as defined in  claim 1  wherein the thromboxane A 2  receptor antagonist is ifetroban and the antiplatelet drug is clopidogrel.  
     
     
         7 . The combination as defined in  claim 1  wherein the antiplatelet drug is employed in a weight ratio to the thromboxane A 2  receptor antagonist within the range of from about 0.001:1 to about 1000:1.  
     
     
         8 . The combination as defined in  claim 1  further including a cholesterol lowering agent.  
     
     
         9 . The combination as defined in  claim 8  wherein the cholesterol lowering drug is an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase.  
     
     
         10 . The combination as defined in  claim 9  wherein said inhibitor of the enzyme HMG CoA reductase is lovastatin, pravastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin.  
     
     
         11 . The combination as defined in  claim 8  wherein the cholesterol lowering drug is a fibric acid derivative.  
     
     
         12 . The combination as defined in  claim 8  wherein the cholesterol lowering drug is gemfibrozil, fenofibrate, clofibrate, bezafibrate, ciprofibrate, clinofibrate, dextrothyroxine or its sodium salt, colestipol or its hydrochloride, cholestyramine, nicotinic acid, neomycin or p-aminosalicylic acid.  
     
     
         13 . The combination as defined in  claim 8  wherein the cholesterol lowering agent is an MTP inhibitor.  
     
     
         14 . The combinaiton as defined in  claim 12  wherein the MTP inhibitor is BMS 201,038 or BMS 212,122.  
     
     
         15 . A method for preventing or inhibiting platelet aggregation and/or thrombus formation in a mammalian species, which comprises administering to a patient in need of treatment a therapeutically effective amount of a pharmaceutical combination as defined in  claim 1 .  
     
     
         16 . A method of preventing or inhibiting onset of an ischemic event which is a cardiovascular, cerebrovascular or peripheral vascular event in a mammalian species, which comprises administering to a patient in need of treatment a therapeutically effective amount of a pharmaceutical combination as defined in  claim 1 .  
     
     
         17 . The method as defined in  claim 16  wherein the ischemic event is a primary or secondary ischemic event.  
     
     
         18 . The method as defined in  claim 16  wherein the ischemic event is a myocardial infarction, unstable angina, stable angina, acute reocclusion after percutaneous transluminal coronary angioplasty, restenosis after percutaneous transluminal coronary angioplasty, thrombotic stroke, transient ischemic attack, reversible ischemic neurological deficit, or intermittent claudication.  
     
     
         19 . The method as defined in  claim 15  wherein the pharmaceutical combination administered comprises an ADP-receptor blocking antiplatelet drug, a thromboxane A 2  receptor antagonist and optionally a cholesterol lowering agent.  
     
     
         20 . The method as defined in  claim 15  wherein the pharmaceutical combination administered comprises an ADP-receptor blocking agent and a thromboxane A 2  receptor antagonist, and optionally aspirin.